Atezolizumab, venetoclax, and obinutuzumab combination in Richter transformation diffuse large B-cell lymphoma (MOLTO): a multicentre, single-arm, phase 2 trial.

in The Lancet. Oncology by Alessandra Tedeschi, Anna Maria Frustaci, Adalgisa Condoluci, Marta Coscia, Roberto Chiarle, Pier Luigi Zinzani, Marina Motta, Gianluca Gaidano, Giulia Quaresmini, Lydia Scarfò, Gioacchino Catania, Marina Deodato, Rebecca Jones, Valentina Tabanelli, Valentina Griggio, Georg Stüssi, Angelica Calleri, Katia Pini, Roberto Cairoli, Thorsten Zenz, Alessio Signori, Emanuele Zucca, Davide Rossi, Marco Montillo

TLDR

  • The study found that a combination of three drugs (atezolizumab, venetoclax, and obinutuzumab) was effective and safe in treating a type of blood cancer called DLBCL-RT. The combination led to a response in 67.9% of patients at cycle 6, and the drugs were well-tolerated. The study suggests that this combination could become a new first-line treatment approach for DLBCL-RT.

Abstract

The diffuse large B-cell lymphoma (DLBCL) variant of Richter transformation (DLBCL-RT) is typically chemoresistant with poor prognosis. Aiming to explore a chemotherapy-free treatment combination that triggers anti-tumour immune responses, we conducted a phase 2 study of atezolizumab (a PD-L1 inhibitor) in combination with venetoclax and obinutuzumab in patients with DLBCL-RT. This was a prospective, open-label, multicentre, single-arm, investigator-initiated, phase 2 study in 15 hospitals in Italy and Switzerland. Eligible patients had a confirmed diagnosis of chronic lymphocytic leukaemia or small lymphocytic lymphoma as per the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria with biopsy-proven transformation to DLBCL; had not previously received treatment for DLBCL-RT, although they could have received chronic lymphocytic leukaemia therapies; were aged 18 years or older; and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. No previous treatment with any of the drugs in the triplet combination was allowed. Patients received 35 cycles of 21 days of intravenous obinutuzumab (100 mg on day 1, 900 mg on day 2, 1000 mg on day 8 and day 15 of cycle 1; 1000 mg on day 1 of cycles 2-8) and intravenous atezolizumab (1200 mg on day 2 of cycle 1 and 1200 mg on day 1 of cycles 2-18), and continuous oral venetoclax (ramp-up from 20 mg/day on day 15 of cycle 1 according to chronic lymphocytic leukaemia schedule, then 400 mg/day from day 1 of cycle 3 to day 21 of cycle 35). The primary endpoint was overall response rate at day 21 of cycle 6 in the intention-to-treat population. We considered an overall response rate of 67% or more to be clinically active, rejecting the null hypothesis of a response of 40% or less. The study is registered with ClinicalTrials.gov, NCT04082897, and has been completed. Between Oct 9, 2019, and Oct 19, 2022, 28 patients were enrolled (12 [43%] male patients and 16 [57%] female patients). Median follow-up was 16·8 months (IQR 7·8-32·0). At cycle 6, 19 of 28 patients showed a response, yielding an overall response rate of 67·9% (95% CI 47·6-84·1). Treatment-emergent adverse events that were grade 3 or worse were reported in 17 (61%; 95% CI 40·6-78·5) of 28 patients, with neutropenia being the most frequent (11 [39%; 21·5-59·4] of 28 patients). Serious treatment-emergent adverse events were reported in eight (29%; 14·2-48·7) patients, which were most commonly infections (five [18%; 6·1-36·9] of 28 patients). There were two (7%) deaths attributable to adverse events during the study: one from sepsis and one from fungal pneumonia, which were not considered as directly treatment-related by the investigators. Six (21·4%) patients had immune-related adverse events, none of which led to discontinuation. No tumour lysis syndrome was observed. The atezolizumab, venetoclax, and obinutuzumab triplet combination was shown to be active and safe, suggesting that this chemotherapy-free regimen could become a new first-line treatment approach in patients with DLBCL-RT. Roche.

Overview

  • The study aimed to explore a chemotherapy-free treatment combination that triggers anti-tumour immune responses in patients with DLBCL-RT. The study was a phase 2, open-label, multicentre, single-arm, investigator-initiated, prospective study in 15 hospitals in Italy and Switzerland. The study population consisted of patients with a confirmed diagnosis of chronic lymphocytic leukaemia or small lymphocytic lymphoma as per the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria with biopsy-proven transformation to DLBCL, who had not previously received treatment for DLBCL-RT, were aged 18 years or older, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. The study used a combination of atezolizumab, venetoclax, and obinutuzumab. The primary endpoint was overall response rate at day 21 of cycle 6 in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT04082897, and has been completed. The study enrolled 28 patients, with a median follow-up of 16.8 months. At cycle 6, 19 of 28 patients showed a response, yielding an overall response rate of 67.9% (95% CI 47.6-84.1). The study found that the atezolizumab, venetoclax, and obinutuzumab triplet combination was active and safe, suggesting that this chemotherapy-free regimen could become a new first-line treatment approach in patients with DLBCL-RT.

Comparative Analysis & Findings

  • The study compared the outcomes observed under different experimental conditions or interventions detailed in the study. The study found that the atezolizumab, venetoclax, and obinutuzumab triplet combination was active and safe, with an overall response rate of 67.9% (95% CI 47.6-84.1) at cycle 6. The study also found that the triplet combination was well-tolerated, with treatment-emergent adverse events that were grade 3 or worse reported in 61% of patients, and serious treatment-emergent adverse events reported in 29% of patients. The study did not find any tumour lysis syndrome, and six patients had immune-related adverse events, none of which led to discontinuation. The study's findings suggest that the atezolizumab, venetoclax, and obinutuzumab triplet combination could become a new first-line treatment approach in patients with DLBCL-RT.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice. The study found that the atezolizumab, venetoclax, and obinutuzumab triplet combination was active and safe, with an overall response rate of 67.9% (95% CI 47.6-84.1) at cycle 6. The study also found that the triplet combination was well-tolerated, with treatment-emergent adverse events that were grade 3 or worse reported in 61% of patients, and serious treatment-emergent adverse events reported in 29% of patients. The study's findings suggest that the triplet combination could become a new first-line treatment approach in patients with DLBCL-RT. Future research could focus on further evaluating the efficacy and safety of the triplet combination in larger patient populations and in combination with other therapies. The study's findings also highlight the importance of continued research into immunotherapy-based treatments for DLBCL-RT.
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